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Updated: Aug 5, 2026

Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies
08:37

Purification and Expansion of Mouse Invariant Natural Killer T Cells for in vitro and in vivo Studies

Published on: February 15, 2021

ITPKB is a conserved regulator of natural killer cell desensitization/education that constrains antitumor immunity

Yeara Jo1, Alexandros Karampatzakis1, Seung Won Lee1

  • 1Division of Immunology and Molecular Medicine, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.

Biorxiv : the Preprint Server for Biology
|July 29, 2026
PubMed

Insights

Persistent stimulation causes Natural Killer (NK) cell desensitization, hindering antitumor immunity. Inhibiting Inositol trisphosphate kinase B (ITPKB) restores NK cell function and enhances tumor control, offering a new therapeutic strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Mechanisms

Background:

  • Persistent stimulation leads to Natural Killer (NK) cell desensitization, compromising durable antitumor immunity.
  • The molecular underpinnings of NK cell dysfunction during chronic activation are not well understood.
  • Identifying regulators of NK cell desensitization is crucial for improving cancer immunotherapy.

Purpose of the Study:

  • To identify conserved molecular regulators of NK cell desensitization.
  • To investigate the role of Inositol trisphosphate kinase B (ITPKB) in NK cell dysfunction.
  • To evaluate the therapeutic potential of targeting ITPKB for enhancing NK cell-mediated antitumor immunity.

Main Methods:

  • Comparative transcriptomic analyses in murine models of persistent NK cell activation.
  • Genetic and pharmacological inhibition of ITPKB in murine and human NK cells.
  • Assessment of NK cell functions including degranulation, cytokine production, and cytotoxicity.
  • Investigation of signaling pathways involving IP3/IP4 axis and calcium mobilization.
  • Evaluation of NK cell-mediated tumor control in vivo and CAR-NK cell efficacy.

Main Results:

  • Transcriptomic analysis identified a shared program of NK cell desensitization, with upregulation of ITPKB.
  • Inhibition of ITPKB restored degranulation, cytokine production, and cytotoxicity in desensitized NK cells.
  • ITPKB regulates NK cell signaling via the IP3/IP4 axis, impacting calcium mobilization and NFAT activity.
  • ITPKB inhibition enhanced NK cell-mediated tumor control in vivo and improved CAR-NK cell therapy efficacy.

Conclusions:

  • ITPKB is a key cell-intrinsic regulator of NK cell desensitization.
  • Targeting ITPKB can overcome NK cell dysfunction induced by persistent stimulation.
  • Modulating the IP3/IP4 signaling axis represents a promising strategy to enhance NK cell-based cancer immunotherapy.

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